WO2013082751A1 - Inhibiteurs i du transport des phosphates - Google Patents

Inhibiteurs i du transport des phosphates Download PDF

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Publication number
WO2013082751A1
WO2013082751A1 PCT/CN2011/083521 CN2011083521W WO2013082751A1 WO 2013082751 A1 WO2013082751 A1 WO 2013082751A1 CN 2011083521 W CN2011083521 W CN 2011083521W WO 2013082751 A1 WO2013082751 A1 WO 2013082751A1
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Prior art keywords
phenyl
chloro
alkyl
trifluoromethyl
group
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PCT/CN2011/083521
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English (en)
Inventor
Morten Dahl SOERENSEN
Jens Christian Hoejland Larsen
Bjarne Noerremark
Xifu Liang
Guoxiang Huang
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Leo Pharma A/S
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Priority to PCT/CN2011/083521 priority Critical patent/WO2013082751A1/fr
Publication of WO2013082751A1 publication Critical patent/WO2013082751A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/22—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of calcitonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel heteroaromatic compounds, to said compounds for use as a medicament, to pharmaceutical compositions comprising said compounds, to methods of preventing, treating or ameliorating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.
  • Phosphate is an essential component of life and fulfils both structural and metabolic roles.
  • Cells obtain phosphorus in the form of negatively charged inorganic phosphate (P,) from the extracellular environment by means of secondary-active transport.
  • P inorganic phosphate
  • transporters use the inwardly directed electrochemical gradient of Na + ions, established by the Na + - K + -ATPase, to drive P, influx.
  • Defects in P, homeostasis may result in severe pathologies.
  • phosphate retention has been shown to play a major role in the progression of renal failure and induction of uremic bone disease and secondary hyperparathyroidism. Diabetes patients are especially at risk, and their number is increasing rapidly.
  • Hyperphosphatemia associated with chronic kidney disease (CKD) is linked tightly to increased risk of cardiovascular morbidity and mortality.
  • a low-phosphate diet has a low compliance due to bad taste and may also lead to nutritional disorders, for example due to lack of ingestion of other nutrients.
  • Representative examples of oral phosphate adsorbents include calcium preparations, magnesium preparations, lanthanum preparations, and aluminum preparations.
  • calcium preparations and magnesium preparations induce hypercalcemia and hypermagnesia, respectively, and tissue accumulation of lanthanum with unknown long-term consequences has been observed for lanthanum preparations.
  • Aluminum preparations induce aluminum osteopathy, aluminum cerebropathy, and dialysis dementia and their use is thus restricted to short-term salvage therapy, i.e. rapid reduction of serum phosphate concentrations.
  • various anion exchange resins have been developed as the oral phosphate adsorbents. Since, however, these anion exchange resins have lower phosphate adsorption capacity than the above group of compounds, a high level of dosage is necessary for phosphate absorption reduction purposes leading to poor patient compliance.
  • Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium-dependent phosphate cotransporter Npt2b (SLC34a2) (J Am Soc Nephrol, 2009, supra). It was shown that Npt2b is largely responsible for intestinal phosphate absorption and contributes to the maintenance of systemic phosphate homeostasis. Thus inhibition of intestinal phosphate absorption by inhibition of the sodium-dependent phosphate transporter Npt2b by a small molecule would be a desirable method to control serum phosphate levels in patients with chronic renal disease or undergoing dialysis.
  • US 2006/017426 discloses compounds inhibiting in vivo phosphorus transport and medicine containing the same.
  • WO 01/05398 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a N-aryl-2- sulfonamidobenzamide compound.
  • WO 01/82924 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a dihydroxybenzamide compound.
  • WO 01/87294 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a N-aryl-2- sulfonamidobenzamide compound.
  • WO 02/28353 discloses thiophene compounds, useful for treatment of chronic renal failure and uremic bone disease.
  • WO 03/048134 discloses triazole compounds and medicinal use thereof as sodium- phosphate cotransporter inhibitors.
  • WO 04/085382 discloses compounds which suppress the concentration of phosphorous in serum.
  • WO 06/0217426 discloses compounds inhibiting in vivo phosphorus transport and medicine containing same.
  • compositions that can effectively prevent or treat diseases induced by an increase in the phosphate concentration of serum by effectively suppressing the phosphate concentration of serum.
  • novel heteroaromatic compounds may inhibit sodium-dependent phosphate transport into cells and may inhibit sodium-dependent phosphate uptake in the small intestine.
  • novel heteroaromatic compounds may inhibit the sodium-dependent intestinal Npt2b transporter.
  • compounds of the present invention may reduce the increase in serum levels of phosphate of mammals to which phosphate have been administered orally.
  • Compounds of the present invention may have improved pharmacokinetic properties such as improved solubility, absorption or stability in comparison to known structurally related compounds.
  • a particular advantage of some of the compounds of the present invention is that they show higher chemical stability in comparison to known structurally related compounds.
  • the present invention relates to a compound according to formula I
  • Ri, R 2 and R 3 each independently are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, COOH, (d-C 4 )alkyl, halo(Ci-C 4 )alkyl, hydroxy(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, cycloalkyl and heterocycloalkyl;
  • R 4 is selected from the group consisting of hydrogen, halogen, (Ci-C 4 )alkyl and heterocycloalkyl;
  • R 5 is selected from the group consisting of hydrogen, COOH, (d-C 6 )alkyl,
  • heterocycloalkyl(Ci-C 6 )alkyl, aryl(Ci-C 6 )alkyl and heteroaryl(Ci-C 6 )alkyl said (Ci- C 6 )alkyl, aryl(Ci-C 6 )alkyl, heterocycloalkyl(Ci-C 6 )alkyl and heteroaryl(Ci-C 6 )alkyl optionally being substituted by one or more substituents selected from R 6 ;
  • R 6 is selected from the group consisting of halogen, -ORa, -SRa, -S(0)Ra, -S(0) 2 Ra, - NRaRb, -N + RaRbRc, -OC(0)Ra, -P(0)(OH) 2 , (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, aryl and a heterocyclic ring; said (Ci-C 6 )alkyl, heterocycloalkyl, cycloalkyl, aryl and heterocyclic ring optionally being substituted by one or more substituents selected from R 7 ; Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, alkoxy(Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and
  • heterocycloalkyl(Ci-C 6 )alkyl comprising (Ci-C 6 )alkyl, alkoxy(Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and heterocycloalkyl(Ci-C 6 )alkyl optionally being substituted by one or more substituents selected from R 7 ;
  • R 7 is selected from the group consisting of hydroxyl, -COOH, -ORd, -NRdRe, -N + RdReRf, and -S0 2 OH;
  • Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, cycloalkyl, heterocycloalkyl and heterocycloalkyl(Ci-C 6 )alkyl; said (Ci- C 6 )alkyl, cycloalkyl, heterocycloalkyl and heterocycloalkyl(Ci-C 6 )alkyl optionally being substituted by one or more substituents selected from halogen, hydroxyl, or cyano;
  • X and Y are selected from the group consisting of CH and N with the proviso that when X represents CH, Y represents N; and with the proviso that when X represents N, Y represents CH; and pharmaceutically acceptable and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof.
  • the invention relates to a compound according to formula
  • R 2 , R 3 , R 4 , X and Y are as defined above and wherein A represents a (C 2 -C 8 ) alkylene chain ;
  • R 8 is selected from the group consisting of hydrogen and (Ci-C 6 )alkyl ; and wherein each occurrence of Ri, R 2 , R3, R 4 , X and Y, respectfully, is identical to any other occurrence of said substituent in the compound of the formula ⁇ .
  • the invention relates to a compound according to the invention for use as a medicament.
  • the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of phosphate homeostasis.
  • the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of age-related arteriosclerosis, anemia, angina pectoris, anomaly of saccharometabolism, arthralgia, bone deformity, calciphylaxis, cardiac induction, cardiovascular calcification, cardiovascular events, chronic kidney disease, diabetic vasculopathy, ectopic calcification, fracture, growth retardation, heart conduction disturbance, heart failure induced by cardiac murmur or valvular disease, hyperlipidemia, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, immune deficiency, metabolic bone disease, metabolic osteopathy, metastatic calcification, muscle damage, myalgia, myoca rdiopathy, nervous system damage induced by PTH increase or Vitamin D lowering, osteoalgia, osteoporosis, progression of renal failure, pruritus cutaneous, pulmonary diffusing impairment, renal failure, renal osteodystrophy, secondary hyperpara
  • the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary
  • hyperparathyroidism hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable vehicle of excipient or pharmaceutically acceptable carrier(s).
  • the invention relates to a use of a compound according to the invention in the manufacture of a medicament for the prophylaxis, treatment or amelioration of calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease.
  • the invention relates to a method of preventing, treating or ameliorating calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease, the method comprising administering to a person suffering from at least one of said diseases or conditions an effective amount of one or more compounds according to the invention, optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.
  • hydrocarbon radical is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties.
  • Said hydrocarbon comprises 1- 10 carbon atoms, and prefera bly comprises 1-8, e.g . 1-6, e.g . 1-4, e.g. 1-3, e.g . 1-2, eg . 2-3 carbon atoms.
  • the term includes alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl and aryl, as indicated below.
  • aryl is intended to indicate a radical of aromatic carbocyclic rings comprising 6- 14carbon atoms, such as 6- 10 carbon atoms or 6-9 ca rbon atoms, in particular 5- or 6-membered rings, including fused ca rbocyclic rings with at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl .
  • heteroaryl is intended to indicate radicals of heterocyclic aromatic rings comprising 1-6 heteroatoms (selected from O, S and N) and 1 - 14 carbon atoms, such as 1-5 heteroatoms and 1- 12 carbon atoms, such as 1-5 heteroatoms and 1-6 carbon atoms, such as 1-4 heteroatoms and 1-3 carbon atoms, in particular 5- or 6-membered rings with 1-4 heteroatoms selected from 0, S a nd N, including fused bicyclic rings with 1-4 heteroatoms, and wherein at least one ring is aromatic, e.g .
  • pyridyl quinolyl, isoquinolyl, indolyl, thiadiazolyl, oxodiazolyl, tetrazolyl, furanyl, thiazolyl, benzooxazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl, benzofuranyl and 6,7,8,9-tetrahydropyrido[2,3-b] [ l,6] naphthyridine.
  • alkyl is intended to indicate a radical obtained when one hyd rogen atom is removed from a hydrocarbon .
  • Said alkyl comprises 1 - 10, preferably 1-8, such as 1-6, such as 1-4, such as 1-3, such as 1-2 carbon atoms or 2-3 carbon atoms.
  • the term includes the subclasses normal alkyl (/7-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, /7-propyl, isopropyl, /7-butyl, isobutyl, sec -butyl, tert.
  • alkylene is intended to indicate a divalent saturated aliphatic hydrocarbyl group preferably having from 2 to 8 carbon atoms that are either straight-chained or branched . This term is exemplified by groups such as ethylene (-CH 2 CH 2 -) or n- propylene (-CH 2 CH 2 CH 2 -) .
  • cycloalkyl is intended to indicate a saturated cycloalkane radical comprising 3-12 carbon atoms, preferably 3-10 carbon atoms, in particular 3-8 carbon atoms, such as 3-6 carbon atoms or 3-5 carbon atoms , including fused bicyclic rings or bridged bicyclic or tricyclic rings, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • heterocycloalkyl is intended to indicate a cycloalkane radical as described above, wherein one or more carbon atoms are replaced by heteroatoms, comprising 1 - 14 carbon atoms, e.g. 2-5 or 2-4 carbon atoms, further comprising 1-6 heteroatoms, preferably 1, 2, or 3 heteroatoms, selected from 0, N, or S, e.g. piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, [ l,3]dioxolanyl and
  • [ l,3]dioxolyl or including fused bicyclic rings with 1-4 heteroatoms, wherein at least one ring comprises a heteroatom, and wherein the other ring may for example be a carbocyclic ring, or including bridged carbocyclic rings, such as e.g. 1,4- diazabicyclo[2.2.2]octane or l,6-diazabicyclo[4.2.2]decane.
  • halogen is intended to indicate a substituent from the 7 th main group of the periodic table, such as fluoro, chloro, bromo and iodo.
  • haloalkyl is intended to indicate an alkyl group as defined above substituted with one or more halogen atoms as defined above, e.g. fluoro or chloro, such as difluoromethyl, or trifluoromethyl.
  • alkoxy is intended to indicate a radical of the formula -OR', wherein R' is alkyl as indicated above, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, etc.
  • haloalkoxy is intended to indicate a radical of the formula -OR', wherein R' is haloalkyl as indicated above, e.g. trifluoromethoxy or difluoromethoxy.
  • hydroxyalkyl is intended to indicate an alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl,
  • heterocyclic ring is intended to include the definitions heteroaryl and heterocycloalkyl as defined above, including annelated ring systems with each other or with cyclic hydrocarbons, e.g. 2,5-dihydrobenzo(b)dioxocine, 2,3,5,8-tetrahydro- [ l,4]dioxocine, 5,8-dihydro-[ l,4]dioxocine, 2,3-dihydro-lH-isoindole, 1,2,3,4- tetrahydropyrido[4,3-b]-[ l,8]-naphthyridine.
  • annelated ring systems e.g. 2,5-dihydrobenzo(b)dioxocine, 2,3,5,8-tetrahydro- [ l,4]dioxocine, 5,8-dihydro-[ l,4]dioxocine, 2,3-di
  • arylalkyl is intended to indicate an alkyl radical as defined above, which is substituted with an aryl radical as defined above, e.g. benzyl, phenylethyl etc.
  • heteroarylalkyl is intended to indicate an alkyl radical as defined above, which is substituted with a heteroaryl radical as defined above, e.g. imidazolylmethyl, pyridinylethyl, etc.
  • heterocycloalkylalkyl is intended to indicate an alkyl radical as defined above, which is substituted with a heterocycloalkyl radical as defined above, e.g.
  • alkoxyalkyl is intended to indicate an alkyl radical as defined above, which is substituted with an alkoxy radical as defined above, i.e. -R'-O-R', wherein each R' is alkyl, same or different, as indicated above, e.g. methoxymethyl, ethoxymethyl.
  • pharmaceutically acceptable salt is intended to indicate salts prepared by reacting a compound of formula I comprising a basic moiety with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroaetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D- glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-l,2-disulfonic, 2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid.
  • a suitable inorganic or organic acid such as hydrochloric, hydrobromic, hydro
  • Pharmaceutically acceptable salts of compounds of formula I comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2- hydroxyethylamine, bis-(2-hydroxyethyl)-amine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example ⁇ , ⁇ '-dibenzylethylenediamine, and dibenzylamine, or L-arginine or L-lysine.
  • a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like
  • suitable non-toxic amines such as lower alkylamines, for example triethyl
  • solvate is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula I, and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a solid form.
  • a solvent e.g. alcohol, glycerol or water
  • water is the solvent
  • said species is referred to as a hydrate.
  • compositions of the invention which comprise free hydroxyl groups or free carboxylic acid groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the present invention.
  • pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiologically conditions to the corresponding compounds of the invention which comprise free hydroxyl groups or free carboxylic acid groups respectively, e.g. in-vivo hydrolysable.
  • R 2 and R 3 each independently are selected from the group consisting of hydrogen, halogen, cyano, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy and heterocycloalkyl.
  • R ⁇ R 2 and R 3 each independently are selected from the group consisting of hydrogen, halogen, cyano, methyl, ethyl, trifluoroalkyl, methoxy, and morpholinyl.
  • R 3 is hydrogen
  • Ri is trifluoromethyl, R 2 is chloro and R 3 is hydrogen.
  • R 4 is selected from the group consisting of halogen and heterocycloalkyl.
  • R 4 is selected from the group consisisting of chloro, bromo and piperidinyl .
  • R5 is selected from the group consisting of hydrogen, COOH,(Ci-C 6 )alkyl, and heterocycloalkyl(Ci-C 6 )alkyl.
  • R 5 is methyl or ethyl. In one or more embodiments of the present invention R 5 is selected from the group consisting of piperazinylalkyl, piperidinylalkyl, and morpholinylalkyl.
  • R 5 is selected from the group consisting of piperazinylmethyl, piperidinylmethyl, and morpholinylmethyl.
  • R 6 is selected from the group consisting of CI, -ORa, -SRa, -S(0)Ra, -NRaRb, -N + RaRbRc, -OC(0)Ra, methyl, ethyl, morpholinyl, piperidinyl and piperazinyl.
  • Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C 6 )alkyl, heterocycloalkyl, heteroaryl, and heterocycloalkyl(Ci-C 6 )alkyl.
  • Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranylmethyl, and triazolyl.
  • R 7 is selected from the group consisting of hydroxyl, -COOH, -NH 2 , -N(CH) 3 + , and -S0 2 OH.
  • Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (d-C 6 )alkyl and
  • heterocycloalkyl(Ci-C 6 )alkyl comprising (Ci-C 6 )alkyl and heteroycloalkyl(Ci-C 6 )alkyl optionally being substituted by one or more hydroxyl.
  • Rd, Re and Rf each independently are selected from the group consisting of hydrogen, methyl and
  • compounds of the formula I according to the invention may be selected from : N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (chloromethyl)benzamide;
  • a compound of the formula I or I ' according to the invention may be used in the prophylaxis, treatment or amelioration of cardiovascular calcification, chronic kidney disease, primary hyperparathyroidism, secondary hyperparathyroidism, hyperphosphatemia or progression of renal failure.
  • compounds of the present invention are typically in the form of a pharmaceutical composition.
  • the invention therefore relates to a pharmaceutical composition comprising a compound of formula I, optionally together with one or more other therapeutically active compound(s), together with a
  • excipient pharmaceutically acceptable excipient, vehicle or carrier(s).
  • the excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the active ingredient comprises from 0.05-99.9% by weight of the formulation.
  • the compound may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner.
  • a dosage unit of a formulation contain between 0.1 mg and 1000 mg, preferably between 1 mg and 100 mg, such as 5-50 mg of a compound of formula I.
  • a suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician.
  • the compound is preferably administered orally according to different dosing schedules, e.g. daily or with weekly intervals. In general a single dose will be in the range from 0.01 to 100 mg/kg body weight.
  • the compound may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or more times a day.
  • administration of a compound of the present invention with one or more other active compounds may be either concomitantly or sequentially.
  • the formulations include e.g. those in a form suitable for oral (including sustained or timed release) administration.
  • the formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 21ed ed., 2005. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or peanut oil.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone.
  • the active ingredients may also be administered in the form of a bolus, electuary or paste.
  • a tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by
  • a binder such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycollate, crospovidone or the like or a dispersing agent, such as polysorbate 80.
  • a binder such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, wax
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
  • the formulations of a compound of formula I Or may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g.
  • methyl hydroxy benzoate (including anti-oxidants), emulsifying agents and the like.
  • preferred salts are for instance easily water-soluble or slightly soluble in water, in order to obtain a particular and appropriate rate of absorption.
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis.
  • the compounds of formula I may for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
  • the reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art.
  • Method A2 Preparative HPLC/MS was performed on a Dionex APS-system with two Shimadzu PP150 prep, pumps and a Thermo MSQ Plus mass spectrometer.
  • Step A Deprotection of the triphenylmethyl protecting group is for example performed under acidic conditions, for example by using 90% AcOH / 10% H 2 0 and microwave heating for an appropriate time and temperature.
  • Step B N-arylation of pyrazole is for example performed under mild copper catalyzed conditions, for example Cul in the presence of sodium ascorbate, (lR,2R)-(-)-l,2- Bis(Methylamino)cyclohexane and DMSO.
  • Step C R 4 , wherein R 4 is nitrogen-containing heterocycloalkyl, is introduced by nucleophile aromatic substitution using an appropriate base, for example DiPEA, NaH or ButOK, and appropriate solvent, for example DMSO, DMF or CH3CN.
  • an appropriate base for example DiPEA, NaH or ButOK
  • appropriate solvent for example DMSO, DMF or CH3CN.
  • the reaction is for example performed under elevated temperature.
  • Step Dl Reduction of the nitrogroup to give the corresponding aniline can for example be performed using NH4CI and Zn or Fe and AcOH or using H 2 in the presence of Pd on carbon.
  • Step D2 Reduction of the nitrogroup in the present of triphenylmethyl protecting group can for example be performed using Zn and NH4CI or Fe and AcOH as reducing agents.
  • Step E Amide coupling can for example be performed by reacting benzoylchloride with an aniline in the presence of a base, for example DIPEA or K2C03, using for example CH2CL2 or DMF as solvent.
  • Step F R 5 , wherein R 5 represents -ORa, -SRa, -NRaRb or heterocycloalkyl, is for example introduced by nucleophilic substitution.
  • the benzylic chloride is for example substituted by an amine in the presence of a base, for example K 2 C0 3 , DIPEA or CsC0 3 , using an appropriate solvent, for example DMSO, DMF, or CH 2 CI 2 as solvent.
  • CHO cells stably expressing full-length human Npt2B (hNpt2B, GenBank accession no. NM_006424) or rat Npt2B (ratNpt2B, GenBank accession no. BC070898) were used to evaluate compounds for their inhibitory activity against sodium-dependent transport of radiolabeled (33P) phosphate.
  • test and negative control wells were incubated with 100 ul assay buffer containing sodium (137 mM NaCI, 5.4 mM KCI, 2.8 mM CaCI 2 , 1.2 mM MgS0 4 , 14 mM Tris HCI, 0.1 mM KH 2 P0 4 , pH 7.4) and 1 uCi/ml 33P-labeled phosphate.
  • Positive control wells were incubated with 100 ul assay buffer containing choline instead of sodium ( 137 mM
  • test compound 1 uCi/ml 33P-labeled phosphate.
  • various concentrations of test compound were loaded to their designated wells.
  • As vehicle control DMSO was loaded to the negative and positive control wells, resulting in a final DMSO concentration of 1% v/v in all 96 wells. After that, the plate was gently agitated at 600 rpm for 1 min and then incubated for 30 min at 30 ° C, followed by 4-times washing with each 150 ul/well ice cold washing buffer (137 mM NaCI, 14 mM Tris HCI, pH 7.4).
  • the relative IC50 value a measure of the potency of the compound in inhibiting the human or rat Npt2B, was obtained from a 4 parameter curve fit and defined as the concentration of compound giving a response midway between the minimal and maximal inhibition.
  • the absolute IC50 value was calculated as the concentration of test compound at which 50% of maximal inhibition of the positive control (sodium replaced by choline,
  • Npt2B phosphate uptake assays The compounds of the present invention were tested in the Npt2B phosphate uptake assays.
  • the absolute IC50 values of the compounds are shown in table 1 Npt2B IC50 ranges:
  • a stock solution of the compound in organic solvent was diluted 1 : 3 using the wanted buffers (pH 2, pH 5, pH 7,4 and/or pH 9) to a concentration of app. 30 mg/ml.
  • the solutions were then portioned out in a number of vials, which remained in the autosampler at room temperature during analysis on HPLC (using a gradient programme and UV-detection).
  • Stability of the compound over time was evaluated using the decrease of Area and Area % of the compound in the chromatograms, whereupon the recovery of the compound was estimated.

Abstract

L'invention concerne des composés de formule (I) qui sont utiles dans le traitement de l'homéostasie des phosphates.
PCT/CN2011/083521 2011-12-06 2011-12-06 Inhibiteurs i du transport des phosphates WO2013082751A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160046568A1 (en) * 2013-04-24 2016-02-18 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
WO2016039458A1 (fr) * 2014-09-12 2016-03-17 中外製薬株式会社 Produit pharmaceutique contenant un inhibiteur de transporteur de phosphate dépendant du sodium
US10053437B2 (en) 2014-09-26 2018-08-21 Daiichi Sankyo Company, Limited Salt of dicarboxylic acid compound
WO2019108800A1 (fr) * 2017-11-29 2019-06-06 The Regents Of The University Of California Composés et méthodes de régénération hématopoïétique
US10822299B2 (en) 2016-05-26 2020-11-03 The Regents Of The University Of California Compounds and methods for hematopoietic regeneration
WO2023219127A1 (fr) * 2022-05-11 2023-11-16 中外製薬株式会社 Composition pharmaceutique pour le traitement ou la prévention d'une maladie kystique

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JPS55113706A (en) * 1979-02-02 1980-09-02 Sankyo Co Ltd Herbicide

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JPS55113706A (en) * 1979-02-02 1980-09-02 Sankyo Co Ltd Herbicide

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BAI, YINJUAN ET AL.: "Microwave-enhanced reaction of 1-phenyl-3- methylpyrazole-5-one with benzoyl chlorides under solvent-free conditions(Chinese)", ORGANIC CHEMISTRY, vol. 22, no. 9, 2002, pages 638 - 641 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160046568A1 (en) * 2013-04-24 2016-02-18 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
US9617232B2 (en) * 2013-04-24 2017-04-11 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
US9670173B2 (en) 2013-04-24 2017-06-06 Daiichi Sankyo Company, Limited Dicarboxylic acid compound
WO2016039458A1 (fr) * 2014-09-12 2016-03-17 中外製薬株式会社 Produit pharmaceutique contenant un inhibiteur de transporteur de phosphate dépendant du sodium
JP5916975B1 (ja) * 2014-09-12 2016-05-11 中外製薬株式会社 ナトリウム依存性リン酸トランスポーター阻害剤を含有する医薬
EP3928779A1 (fr) 2014-09-12 2021-12-29 Chugai Seiyaku Kabushiki Kaisha Proproduits pharmaceutiques contenant un inhibiteur de transporteur de phosphate dépendant au sodium et un adsorbant de phosphore devant être utilisés pour la prévention, le traitement ou la suppression des maladies rénales chroniques, de l'artériosclérose associée à la calcification vasculaire ou de la calcification ectopique.
US10053437B2 (en) 2014-09-26 2018-08-21 Daiichi Sankyo Company, Limited Salt of dicarboxylic acid compound
US10822299B2 (en) 2016-05-26 2020-11-03 The Regents Of The University Of California Compounds and methods for hematopoietic regeneration
WO2019108800A1 (fr) * 2017-11-29 2019-06-06 The Regents Of The University Of California Composés et méthodes de régénération hématopoïétique
WO2023219127A1 (fr) * 2022-05-11 2023-11-16 中外製薬株式会社 Composition pharmaceutique pour le traitement ou la prévention d'une maladie kystique

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